The objectives of this application are: to describe the capability of the Hospital for Sick Children/University of Toronto site as a Clinical Center for TrialNet and to describe studies to determine whether intravenous treatment with glutamic acid decarboxylase (GAD) alters the immune response directed at islet cells thereby preventing ongoing B cell destruction in two groups of subjects: (1) patients with newly diagnosed Type 1 diabetes (DM1), using preservation of C-peptide secretion as the primary endpoint (Intervention); and (2) relatives of patients with DM1 who are at significant risk of diabetes, as defined by the presence of two islet antibodies, using prevention/delay of loss of first phase insulin release as the primary endpoint (Prevention). The clinical center includes: Principal and Co-investigators Drs. Diane Wherrett, Denis Daneman and Jeffrey Mahon, who have extensive experience in clinical trials, diabetes prevention trials, study design and immunology of Type 1 diabetes; the strong infrastructure of the Hospital for Sick Children Research Institute which provides the facilities, clinical trials, methodological and statistical support and scientific environment to carry out these studies; a network of pediatric and adult institutions within the Greater Toronto Area and beyond which will supply a large subject pool for study participation and have a proven track record of high levels of participation in diabetes prevention trials, both in ENDIT and DPT-1. The Intervention study will use a randomized, double-blind, placebo-controlled design to assess the efficacy and safety of parenteral GAD to maintain residual insulin secretion in persons with new-onset DM1. 132 patients with DM1 will be identified within 4 weeks of onset of insulin therapy. They will be randomized 2:1 to 2 different doses of GAD or placebo. The study endpoint will compare the mean meal-stimulated C-peptide level at 12 months in the GAD treated group versus placebo by a two-sided t-test. An interim analysis for safety will be carried out. The Prevention study will use a randomized, double-blind, placebo-controlled design to assess the efficacy of parenteral GAD in the prevention of loss of first phase insulin release in first degree relatives of those with Type 1 diabetes. It involves: screening first degree relatives for antibodies to insulin, IA-2, and GAD (and ICA in those with 1 positive antibody), if 2 of GAD, IA-2 or insulin antibodies are greater than the 97th percentile, then; staging with intravenous glucose tolerance test (IVGTT) to measure first phase insulin release (FPIR), HLA typing to exclude DQB10602 and confirmation of islet antibody status, if FPIR is greater than the 1st percentile for age and normal oral glucose tolerance, then; randomization 1:1 to intervention with GAD or control; follow up with IVGTT every 6 months, repeated if less than the 1st percentile, if confirmed, subject has reached study endpoint. The primary analysis will test the difference in proportion of subjects and controls with FPIR below 1st percentile for age, using a two-sided Chi Square test with continuity correction.